Progressive multifocal leukoencephalopathy (PML) is a rare, fatal demyelinating disease of the brain caused by the polyomavirus JC (JCV) under immunosuppressive conditions. It is pathologically characterized by progressive damage of white matter of the brain by destroying oligodendrocytes at multiple locations. Clinically, PML symptoms include weakness or paralysis, vision loss, impaired speech, and cognitive deterioration. Severe inflammation can result in brain edema and lead herniation and death of the patients (Tan et al., 2009). The prognosis of PML is generally poor. The lifespan for PML patients averaged 9 months for non-AIDS patients and 2 to 4 months for these with HIV infection before antiretroviral drugs were available. The mortality rate of PML is still nearly 50% in HIV-infected patients with antiretroviral therapy (Ferenczy et al., 2012). Although 39% to 58% of the general population are seropositive for antibodies to JCV (Kean et al., 2009, Egli et al., 2009), PML occurs only under immune suppression conditions, such as AIDS patients (Cinque et al., 2009), transplant patients using immunosuppressive medicines (Mateen et al., 2011), certain chemotherapy with immune system damage (Pruitt, 2012), and using natalizumab for multiple sclerosis (Major E. 2010; Sadiq et al., 2010), etc.
No effective therapy for PML has been established, although it is a fatal disease. The current strategies to develop PML therapy focuses on blocking the way of viral infection or the inhibition of JCV replication (Marshall and Major, 2010). Blockage of JCV entry via 5HT2AR with receptor antagonists, chlorpromazine and clozapine, effectively inhibited JCV infection (Elphick et al., 2004, Schaumburg et al., 2008, O'Hara et al., 2008, Nukuzuma et al., 2009). Since these are antagonists to other receptors (e.g. dopamine, histamine, adrenergic and acetylcholine receptors) as well, their effect is nonspecific and causes serious side effect and toxicity. Further, although controlled trials have not yet been performed, the clinical efficacy of these compounds seems poor. Several nucleoside analogs, including azidothymidine, acyclovir, CMX001, cidofovir, Ara-A, and Ara-C) have been used for inhibition of JCV replication (Marshall and Major, 2010; Ferenczy et al., 2012). However, these drugs can not only disrupt viral DNA synthesis but cellular DNA synthesis of host as well. With the limited access to the CNS, the therapeutic dose of drug would result in severe side effect in vivo. Anti-inflammatory agents including diclofenac sodium, mefanamic acid and flunixin meglumine, antimalarial drug mefloquine, and the antineoplastic drug isotretinoin have been shown to inhibit JCV replication in vitro. Although mefloquine is the sole drug passing through the blood-brain barrier (Jones et al. 1994; Pham et al. 1999) among these agents, it elicits broad neurotoxicity (Toovry, 2009) and has not shown efficacy in a clinical trial in PML patients (Clifford et al. 2013).
Reports have indicated that in vitro, RNAi may have shown some promise in reducing JC virus replication (Radhakrishnan 2004). However, the RNAi agents examined were not designed against all known JC Virus strains and were not selected for stability and other properties need for in vivo therapeutic RNAi agents. Accordingly, despite significant advances in the field of RNAi, there remains a need for an agent that can selectively and efficiently silence a gene in the JC virus that has both high biological activity and in vivo stability, and that can effectively inhibit replication of the JC virus for use in treating pathological processes mediated by JC virus infection.